Phase III Study Showed Rituxan® Decreased The Progression Of Joint Damage In Patients With Early Rheumatoid Arthritis

Genentech, Inc. (NYSE:DNA) and Biogen Idec (Nasdaq:BIIB) announced today that a Phase III clinical study of Rituxan® (rituximab) in patients with early rheumatoid arthritis (RA) who have not previously been treated with methotrexate (MTX) met its primary endpoint.

In this study, known as IMAGE, patients received two infusions of either 500 mg or 1000 mg of Rituxan or placebo for up to two treatment courses in combination with a stable dose of MTX. At week 52, only patients in the 1000 mg treatment group met the primary endpoint and showed significantly less progression of joint damage compared to patients who received placebo in combination with MTX. Joint damage was assessed by changes in X-ray images using the Genant-modified total Sharp score.

In both Rituxan treatment groups, secondary endpoints showed a significantly higher proportion of patients with a substantial improvement in RA signs and symptoms (including ACR scores and DAS remission) compared to patients receiving MTX alone. Further analyses of the data are ongoing and will be submitted for presentation at an upcoming medical meeting.

“The study results with Rituxan plus methotrexate in this early RA population are important because the majority of joint damage — a leading cause of disability in patients with RA — is believed to occur within the first two years of the disease, often before traditional disease-modifying drugs like methotrexate have been prescribed,” said Hal Barron, M.D., Genentech’s senior vice president, Development and chief medical officer. “The results from IMAGE reinforce our belief that B cells play an important role in the underlying disease process in RA.”

“The IMAGE study results provide further support for initiating a B-cell targeted agent earlier in RA treatment,” said Evan Beckman, M.D., Biogen Idec’s senior vice president of Immunology Research and Development. “The study results also confirm Rituxan’s positive impact on disease activity and physical function in RA patients. We look forward to sharing the full data set with the medical community and the FDA.”

The safety profile of Rituxan was consistent with our previous experience and a preliminary analysis did not reveal any new or unexpected safety signals. The incidence of adverse events and serious adverse events including infections and serious infections were comparable between Rituxan and placebo treatment groups. The companies continue to monitor the long-term safety of Rituxan treatment.

About the IMAGE Study

IMAGE is a multi-year, Phase III, randomized, double-blind, placebo-controlled, parallel group, multicenter international study designed to evaluate the safety and efficacy profile of Rituxan in combination with a stable dose of MTX compared to MTX alone, in methotrexate-na??ve patients with active rheumatoid arthritis. Methotrexate is a commonly used disease-modifying, anti-rheumatic drug (DMARD). The primary objective of the study was to determine the efficacy of Rituxan in the prevention of progression of structural joint damage and to evaluate the safety of Rituxan in patients with active, early rheumatoid arthritis initiating treatment with MTX.

A total of 755 MTX-na??ve patients with active RA from 168 study sites across 27 countries were randomized to receive either Rituxan (500 mg or 1000 mg) or placebo by intravenous infusion on days 1 and 15, in addition to therapy with MTX. Eligible patients who were not in DAS28-ESR remission 24 weeks following their previous course received a further course of RTX with the same dose as the first course. The primary endpoint evaluating change in total Genant-modified total Sharp scores was measured at week 52.

About Rheumatoid Arthritis (RA)

RA is a debilitating autoimmune disease that affects an estimated 1.3 million Americans and hinders daily activities. The damage that occurs in RA is a result of the immune system attacking joint tissue, causing painful chronic inflammation and irreversible destruction of cartilage, tendons and bones, which often results in disability. Common RA symptoms include inflammation of the joints, swelling, fatigue, stiffness and pain. Additionally, since RA is a systemic disease, it can affect other tissues such as the lungs and eyes.

About Rituxan®

Rituxan, discovered by Biogen Idec, is a therapeutic antibody that first received FDA approval in November 1997 for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B cell non-Hodgkin’s lymphoma. It was also approved in the European Union under the trade name MabThera® in June 1998. Rituxan received FDA approval in February 2006 for the treatment of diffuse large B-cell lymphoma (DLBCL) in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens in previously untreated patients.

In February 2006, Rituxan also received FDA approval in combination with MTX to reduce signs and symptoms in adult patients with moderately-to-severely active RA who have had an inadequate response to one or more TNF antagonist therapies. In January 2008, Rituxan was approved to slow the progression of structural damage in adult patients with moderately-to-severely active RA who have had an inadequate response to one or more TNF-antagonist therapies. Rituxan is the first treatment for RA that selectively targets immune cells known as CD20-positive B cells. Rituxan does not target the entire immune system.

CD20 is not found on stem cells, pro-B cells (B cell precursors), normal plasma cells, or other normal tissues. Rituxan does not target plasma cells. These cells make antibodies that help fight infections.

Rituxan does not target stem cells in the bone marrow, and B cells can usually regenerate and gradually return to normal levels after retreatment with Rituxan in about 12 months for most patients.

In addition, Rituxan received FDA approval in September 2006 for first-line treatment of previously-untreated patients with follicular NHL in combination with CVP (cyclophosphamide, vincristine, and prednisolone) chemotherapy and also for the treatment of low-grade NHL in patients with stable disease or who achieve a partial or complete response following first-line treatment with CVP chemotherapy.

Over the past ten years, there have been more than 1 million patient exposures to Rituxan.

Rituxan is also being studied in other autoimmune diseases with significant unmet medical needs, including lupus nephritis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

Rituxan Safety

Rituxan has been associated with fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML).

Hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation have also been observed. Patients should be closely observed for signs of infection if biologic agents and/or disease modifying anti-rheumatic drugs (DMARDs) other than methotrexate are used concomitantly.

The most common adverse reactions in Rituxan-treated RA patients are hypertension, nausea, upper respiratory tract infection, arthralgia, pruritus, and pyrexia.

The most common adverse reactions (incidence ?‰? 25 %) in Rituxan-treated NHL patients are infusion reactions, fevers, chills, infection, asthenia, and lymphopenia.

For additional safety information, please see full prescribing information, including Boxed Warnings and Medication Guide available at 1-800-821-8590 or gene

About Genentech

Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines for patients with significant unmet medical needs. The company has headquarters in South San Francisco, California and is listed on the New York Stock Exchange under the symbol DNA. For additional information about the company, please visit gene.

About Biogen Idec

Biogen Idec creates new standards of care in therapeutic areas with high unmet medical needs. Founded in 1978, Biogen Idec is a global leader in the discovery, development, manufacturing, and commercialization of innovative therapies. Patients in more than 90 countries benefit from Biogen Idec’s significant products that address diseases such as lymphoma, multiple sclerosis, and rheumatoid arthritis. For product labeling, press releases and additional information about the company, please visit biogenidec

View drug information on Rituxan.

Mayo Study Examines Link Between Rheumatoid Arthritis And Chronic Lung Diseases

For decades, researchers have suspected a connection between chronic lung diseases and rheumatoid arthritis (RA). Previous research has yielded widely varying estimates about the strength of this connection, partly because studies have used different diagnosis criteria for these diseases. Addressing this problem, Mayo researchers presented preliminary data at the American College of Rheumatology Annual Meeting confirming that patients with rheumatoid arthritis are clearly affected by chronic lung diseases.

The goal of this study is to more precisely measure the cumulative incidence of lung diseases among people with rheumatoid arthritis. Mayo researchers studied a group of 603 people who met strict American College of Rheumatology Annual Meeting diagnosis criteria for RA, examining the subjects’ medical records from diagnosis through their death or last follow-up appointment.

Two pulmonologists and two rheumatologists also studied the subjects’ records for evidence of chronic lung disease. Using a list of strict diagnosis criteria, individual physician’s diagnoses, pulmonary function testing results, X-rays and biopsy findings, they estimated the cumulative incidence of obstructive lung disease and diffuse parenchymal infiltrative lung disease (DPILD) in the study group.

Significant findings

A total of 603 RA subjects were followed for a median of 14 years. The cumulative incidence of obstructive lung disease using the list of diagnosis criteria was 4.1 percent at 10 years after RA diagnosis, 9.5 percent at 20 years and 15.5 percent at 30 years. The observed incidence of DPILD using these criteria was even higher: 7.2 percent, 15.5 percent and 22.4 percent after 10, 20, and 30 years, respectively.

“Having good data that supports a link between rheumatoid arthritis and chronic lung diseases is just the first step,” says Eric Matteson, M.D., Mayo rheumatologist and the study’s lead researcher. “We now need additional research to explore the most effective treatment strategies for these patients and to clarify how these diagnoses impact the quality of life and incidence of mortality in these patients.”

Collaboration and support

The Mayo Clinic research team also included: Yimi Medina, Cynthia Crowson, Sara Achenbach, Sean Caples, D.O., Jay Ryu, M.D., Sherine Gabriel, M.D., and Tim Bongartz, M.D. This work was supported in part by grants from the Mayo Foundation.

Contact: Sara Lee

Mayo Clinic

Kamada Completes Enrollment In Its Phase II Bronchiectasis Trial With Inhaled AAT

Kamada (TASE:KMDA), a biopharmaceutical company engaged in the development, production and marketing of specialty life-saving biotherapeutics, announced recently that it has completed patient enrollment in its Phase II clinical trial evaluating treatment of bronchiectasis patients with inhaled Alpha-1 Antitrypsin (AAT) delivered by the investigational eFlow® nebulizer system (PARI Pharma GmbH).

Chief Executive Officer of Kamada, David Tsur, said, “We are very pleased with the progress of this study and look forward to its upcoming completion. We believe that Kamada’s AAT delivered by PARI’s eFlow® has the potential to become a novel treatment for bronchiectasis. Kamada is committed to the development of inhaled AAT to treat bronchiectasis and to proceed with its ongoing clinical efforts in Alpha 1 Antitrypsin Deficiency and Cystic Fibrosis.”

About the study

A total of 21 patients with brochiectasis were enrolled and randomized into this , double-blind, placebo controlled Phase II study. The purpose of the trial is to investigate safety and efficacy of inhaled AAT in this patient population.

About Kamada’s Inhaled AAT

Kamada’s AAT product has the advantages of a high purity preparation combined with a liquid, ready to use, presentation that does not include stabilizers or preservatives. Efficacy trends towards reduction in lung inflammation were also shown recently by inhaled AAT in a phase II cystic fibrosis study sided to a high safety profile for the given study period.

Kamada’s inhaled AAT, which is delivered via an optimized Investigational eFlow Nebulizer System (PARI Pharma GmbH), has received Orphan Drug Designation from the US FDA for the bronchiectasis indication.

About Bronchiectasis

Bronchiectasis is an abnormal stretching and enlarging of the airways. Bronchiectasis patients usually suffer from recurrent, severe episodes of bronchitis, chronic cough and sputum production. According to the US COPD foundation approximately 600,000 individuals suffer from bronchiectasis worldwide, with an estimated 100,000 people in the US alone (excluding cystic fibrosis patients).

About PARI Pharma and the Investigational eFlow® Nebulizer System

Kamada’s Inhaled AAT is delivered by the Investigational eFlow Nebulizer System (PARI Pharma GmbH). The Investigational eFlow Nebulizer System uses eFlow Technology to enable extremely efficient aerosolization of liquid medications via a vibrating, perforated membrane that includes thousands of small holes that produce the aerosol mist. Compared to other nebulization technologies, eFlow Technology produces aerosols with a very high density of active drug, a precisely defined droplet size, and a high proportion of respirable droplets delivered in the shortest possible period of time. Combined with its silent mode of operation, small size (it fits in the palm of your hand), light weight, and battery use, eFlow Technology reduces the burden of taking daily, inhaled treatments. The Investigational eFlow Nebulizer System and eFlow Technology are proprietary to PARI Pharma and can be optimized to specific drug formulations.

PARI Pharma focuses on the development of aerosol delivery devices and therapies. Based on PARI’s 100-year history working with aerosols, PARI Pharma develops treatments for pulmonary and nasal administration optimized with advanced delivery technologies, such as eFlow technology. Online at PariPharma.

About Kamada

Kamada is a public biopharmaceutical company (kamada) developing, producing and marketing a line of specialty life-saving biopharmaceuticals using its proprietary chromatographic purification technologies. Several of these specialty therapeutics are currently undergoing advanced clinical trials.

Eyal Leibovitz

Asthma UK Cymru Launches Report On The State Of Asthma Services And Care In Wales

Asthma UK Cymru is launching a report ‘A Quarter of a Million Voices??¦.and Counting’, which outlines the challenges facing people with asthma in Wales today and highlights the need for asthma health services in Wales to be vastly improved.

Rates of asthma in Wales are among the highest in the world, with 1 in 12 adults and 1 in 10 children living with the condition. The country also has some of the highest hospital admissions for asthma in the world, with more than 4,000 admissions every year.

While key improvements to the lives of people with asthma are highlighted in the report, new research reveals that:

- An alarming 75% of people with asthma in Wales today do not have a personal asthma action plan, yet many of these people wish to have one.

People with such a plan are four times less likely to require a hospital admission for their asthma and the ‘Service Development and Commissioning Directives: Chronic Respiratory Conditions’ specify that by September 2008, all patients in Wales with chronic respiratory conditions should have individual care plans in place developed between the patient and their healthcare professional.

Asthma UK has personal asthma action plans that can be used as a quick and effective way to assist the introduction of care-plans across Wales.

- People with asthma living in deprived areas of Wales, such as Blaenau Gwent, are most likely to feel that their asthma is out of control, to say that the condition has limited their lives and to have lower expectations of how their asthma treatment can help their condition.

- Despite the advances in asthma medicine and treatment over recent years, 24% of people with asthma feel there is nothing they can do to limit their asthma symptoms and one in seven feel the condition has a negative impact on how other people see them.

Janet Pardue-Wood, National Director of Asthma UK Cymru says: ‘While free prescriptions and smoke-free legislation have helped to ease the burden on the lives of people with asthma in Wales, our report clearly shows there is much more work to be done. When asthma is not controlled effectively, the effects can be devastating and in some cases fatal, which is why improving healthcare and reducing the hospital admissions of the 260,000 people with asthma in Wales is a key aim for Asthma UK Cymru. Our new report “A Quarter of a Million Voices??¦.and Counting” aims to celebrate key policy changes that have made a positive impact on people with asthma in Wales, and highlight how we can further improve their lives.’

Abigail Foster, who has asthma, says: ‘I’m proud to have been part of Asthma UK Cymru’s campaign for free prescriptions, which has made such a difference to people with asthma in Wales. Although my asthma is quite well controlled, I still need six medicines at the moment to do this. If I still had to pay for all these medicines it would soon add up. And if someone like me, who earns an ok wage and makes sure they’ve got their asthma under control, thinks twice about the cost of their medicine, what about someone struggling financially?’

The report will be launched at Asthma UK Cymru’s third birthday event at the Senedd on Tuesday 24 June. Asthma UK Cymru will be joined on the evening by children from Lansdowne Primary School who will demonstrate the impact key policy changes have made on people with asthma during their play ‘Asthma in the limelight’. Guests will include Assembly Members, healthcare professionals and people with asthma.


1. The production of the report ‘A Quarter of a Million Voices??¦.and Counting’ has been sponsored by an educational grant from GlaxoSmithKline.

2. Asthma UK Cymru’s third birthday event at the Senedd is supported by an educational grant from Novartis.

3. For further information, contact the Asthma UK Media Office on 020 7786 4949 or at mediaofficeasthma or the Wales office on 02920 435400.

4. Asthma UK is the charity dedicated to improving the health and well-being of the 5.2 million people in the UK whose lives are affected by asthma. Asthma UK Cymru is dedicated to improving the health and well-being of the 260,000 people in Wales whose lives are affected by asthma.

5. For up-to-date news on asthma, information and publications, visit the Asthma UK website asthma.

6. For independent and confidential advice on asthma, call the Asthma UK Adviceline, which is staffed by asthma nurse specialists. It is open weekdays from 9am to 5pm on 08457 01 02 03. Or email an asthma nurse at asthma/adviceline.

Asthma UK

$1.4 Billion In Assistance To Bogus Hurricane Victims

The American Government has handed out $1.4 billion’s worth of hurricane assistance to bogus claimants. The list of dishonest claimants includes people who managed to acquire football season tickets, vacations, legal help for a divorce, to a prisoner who used a cemetery as his home address claiming to be a hurricane victim.

It seems that 16% of the money handed out did not actually make its way to real hurricane victims, according to a General Accountability Office (GAO) inquiry. Some GAO officials went undercover and found out how easy it was to con the system and get payments from FEMA (Federal Emergency Management Agency). One of the agents managed to make up a fake address and get a $2,358 treasury cheque for rental assistance. Even when FEMA found out the agent did not live at that address it still went ahead with the payment.

The list of scams is like something out of a fiction novel. One claimant managed to get money that paid for a 70-day vacation in a hotel in Hawaii.

Michael, McCaul, chairman of the subcommittee that will conduct a hearing in the House of Representatives today said “This is an assault on the American taxpayer. Prosecutors from the federal level down should be looking at prosecuting these crimes and putting the criminals who committed them in jail for a long time.”

FEMA received a lot of criticism for its slow response to the Katrina disaster. It seems it will be in for even more criticism now. A FEMA spokesman said that it takes the stewardship of looking after taxpayers’ dollars very seriously. He added that FEMA is careful to make sure funds are distributed appropriately.

Although FEMA puts the amount of wrong payments at about $16 million, the GAO says it is almost sure the figure is around $600 million to $1.4 billion. There were many cases of people being paid for their hotel stay while at the same time receiving emergency rental assistance. There were other cases of people being paid thousands of dollars for their stay in a hotel while at the same time receiving rental assistance for multiple locations.

To try to claw back a possible one billion dollars or more will be a monumental task. How many people were involved in scams? If the number is high, the total Katrina bill is going to be massive. To the total amount raised and given out, add to this the bill of trying to get back the money that went to fraudsters, and then add to this the cost of taking them to court for their crimes.


New Diagnostic Criteria For Alzheimer’s Disease

An international group of Alzheimer’s disease (AD) experts have proposed new criteria for the reasearch diagnosis of the condition, as they argue the existing criteria are out of date due to unprecedented growth of scientific knowledge in the field. The proposal is put forward in a Position Paper published early Online and in the August edition of The Lancet Neurology.

AD is a neurodegenerative disease characterised by progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatric symptoms or behavioural changes. It is the most common form of dementia.

The existing criteria were published in 1984 by the National Institute of Neurological Disorders and Stroke-Alzheimer Disease and Related Disorders (NINCDS-ADRDA) working group.

Dr Bruno Dubois, Salp??tri??re Hosptial, Paris, France, and colleagues, say: “[These existing criteria] are the prevailing diagnostic standards in research; however they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET*, and cerebrospinal fluid analyses.”

To meet the new criteria for probable AD, patients must show progressive memory loss over more than six months, plus at least one or more of the supportive biomarker criteria. These include: atrophy in a particular part of the brain shown by MRI, abnormal biomarker proteins in the cerebrospinal fluid, a specific pattern on PET of the brain, and a genetic mutation for AD within the immediate family. The authors say: “These new criteria are centred on a clinical core of early and significant episodic memory impairment??¦the timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis.”

The researchers add that validation studies are required to advance the new criteria and optimise their sensitivity, specificity and accuracy.

They conclude: “When effective disease-modifying medications are available, the argument for such biologically based studies will be even more compelling.

“These proposed criteria move away from the traditional two-step approach of first identifying dementia according to degree of functional disability, and then specifying its cause. Rather, they aim to define the clinical, biochemical, structural, and metabolic presence of AD.”

In an accompanying Comment, Dr Norman Foster, Center for Alzheimer’s Care, Department of Neurology, University of Utah, USA says: “We should seize this opportunity to reopen the discussion of Alzheimer’s disease diagnosis. The time is right to use the advanced technology at our disposal to improve the early, accurate diagnosis of dementia and develop more effective treatments.”

PET*= Positron Emission Topography

The Lancet Neurology

Link Between Pain Thresholds, Inflammation And Sleep Problems In Arthritis Patients

Despite recent advances in anti-inflammatory therapy, many rheumatoid arthritis (RA) patients continue to suffer from pain. Research published in BioMed Central’s open access journal, Arthritis Research & Therapy found that inflammation is associated with heightened pain sensitivity at joint sites, whereas increased sleep problems are associated with heightened pain sensitivity at both joint and non-joint sites.

Researchers from the Division of Rheumatology and Pain Management Center of Brigham and Women’s Hospital, and the Chronic Pain and Fatigue Center of the University of Michigan Medical School, assessed experimental pain sensitivity, disease activity, sleep problems and psychiatric distress in 59 women with RA. The researchers used questionnaires to assess the women’s sleep problems and psychiatric distress and measured the levels of C-reactive protein as an indicator of disease activity. They also measured pain sensitivity with pressure pain threshold testing at joint and non-joint sites. Lower pain thresholds are indicative of higher pain sensitivity.

“Sleep problems were inversely associated with pain threshold at all sites, suggesting a defect in central pain processing”, state the authors. This finding emphasises the need for research into the mechanisms underlying sleep disorders and pain in RA patients, particularly given the common occurrence of sleeping problems among these patients. This autoimmune disease, causing chronic inflammation, affects nearly 1% of the population and sufferers often report ongoing pain in spite of successful anti-inflammatory treatment.

“Since differences in pain sensitivity may shape the course of pain complaints and influence treatment decisions, it is important to understand the factors associated with enhanced pain sensitivity”, lead author Yvonne Lee says, adding, “Physicians and researchers should consider both inflammatory and non-inflammatory factors when evaluating pain in research settings and in the clinic.”


The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study
Yvonne C Lee, Lori B Chibnik, Bing Lu, Ajay D Wasan, Robert R Edwards, Anne H Fossel, Simon M Helfgott, Daniel H Solomon, Daniel J Clauw and Elizabeth W Karlson
Arthritis Research & Therapy (in press)

Charlotte Webber

BioMed Central

News From The Journal Of Clinical Investigation July 1, 2008

Calpain inhibitors never forget: improving memory in Alzheimer disease mice

Overactivation of proteins known as calpains, which are involved in memory formation, has been linked to Alzheimer disease. Ottavio Arancio and colleagues, at Columbia University, New York, have now shown that two different drugs that inhibit calpains can improve memory in a mouse model of Alzheimer disease (APP/PS1 mice), leading them to suggest drugs that target calpains might stop or slow down the memory loss that occurs as Alzheimer disease progresses.

It is thought that dysfunctional signaling between nerve cells contributes to the impaired cognition experienced by individuals with Alzheimer disease. In the study, analysis of cells and tissue slices from APP/PS1 mice, specifically cells from the part of the brain known as the hippocampus and hippocampal slices, indicated that exposure to calpain inhibitors restored signaling between nerve cells to normal. The authors therefore suggest that calpain inhibitors improve memory in APP/PS1 mice because they reestablish normal signaling between nerve cells.

TITLE: Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease

Ottavio Arancio
Columbia University, New York, New York, USA.

View the PDF of this article at: https://the-jci/article.php?id=34254

Bringing stability to the protein defective in phenylketonuria

Phenylketonuria (PKU) is an inherited disease characterized by progressive mental retardation and seizures because the individual is deficient in the protein PAH. Most of the genetic mutations that cause PKU do so because the PAH protein that is generated by the mutated gene is not stable enough to function. New data, generated by Aurora Martinez and colleagues, at the University of Bergen, Norway, suggest that it might be possible to stabilize the mutated PAH protein in individuals with PKU such that it can function normally.

In the study, a high-throughput screen for small molecules that stabilized mutated forms of the PAH protein found in individuals with PKU identified four potential candidates. Two of these molecules were analyzed in more detail and shown to stabilize both normal and mutated PAH in their functional conformation. In addition, these molecules increased the activity and amount of normal PAH and mutated PAH expressed in human cells in vitro and increased PAH activity in the liver of mice. The authors therefore suggest that molecules that stabilize PAH (which are known as chaperones) might provide a new approach to the treatment of individuals with PKU.

TITLE: Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria

Aurora Martinez
University of Bergen, Bergen, Norway.

Javier Sancho
Universidad de Zaragoza, Zaragoza, Spain.

View the PDF of this article at: https://the-jci/article.php?id=34355

FGF8 mutations linked to diseases caused by deficiency of a hormone needed for reproduction

New data, generated by Nelly Pitteloud and colleagues, at Massachusetts General Hospital, Boston, has identified mutations in the FGF8 gene in individuals with idiopathic hypogonadotropic hypogonadism (IHH), a disease characterized by failed sexual maturation and infertility due to a deficiency in the small protein gonadotropin-releasing hormone (GnRH).

Six different mutations in FGF8 were identified in individuals with IHH and were associated with slightly different symptoms and varying degrees of GnRH deficiency. When mice expressing markedly reduced levels of FGF8 (approximately 55% less than normal) were analyzed they were found to lack nerve cells producing GnRH in a region of the brain known as the hypothalamus. By contrast, mice expressing slightly more FGF8 did have nerve cells producing GnRH in the hypothalamus, although fewer than normal mice. These data led the authors to conclude that FGF8 is important for the development of nerve cells producing GnRH in both mice and humans and that mutations in FGF8 can lead to GnRH deficiency and disease in humans.

TITLE: Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice

Nelly Pitteloud
Massachusetts General Hospital, Boston, Massachusetts, USA.

View the PDF of this article at: https://the-jci/article.php?id=34538

New way to predict prostate cancer spreading

For men, one of the leading causes of death from cancer is prostate cancer that has spread to a second site (something known as metastatic prostate cancer). Defining the molecular mechanisms by which the initial tumor becomes able to spread to a new site (a process known as metastasis) is likely to help clinicians predict an individual’s chance of survival and help researchers develop new therapies. New data, generated by John Martignetti and colleagues, at Mount Sinai School of Medicine, New York, has identified a specific form of the protein KLF6 (KLF6-SV1) as indicative of poor survival in men with prostate cancer.

The information in genes is converted into a protein via an intermediate known as mRNA. In the study, analysis of tumors from men with localized prostate cancer who had undergone a prostatectomy revealed that increased levels of an mRNA intermediate involved in the generation of KLF6-SV1 correlated with more rapid disease recurrence and decreased survival. Consistent with this having an important role in metastasis, prostate cancer cells expressing increased levels of KLF6-SV1 metastasized more rapidly and more often than normal prostate cancer cells in two mouse models of metastatic prostate cancer. Conversely, decreasing KLF6-SV1 expression in prostate cancer cells decreased tumor growth in mice. The authors therefore suggest that measuring KLF6-SV1 expression levels in prostate cancer tumors at the time of diagnosis might help clinicians predict whether or not the tumor will metastasize and that targeting KLF-SV1 might provide a new avenue for the development of therapeutics to treat individuals with prostate cancer.

TITLE: KLF6-SV1 overexpression accelerates human and mouse prostate cancer progression and metastasis

John A. Martignetti
Mount Sinai School of Medicine, New York, New York, USA.

View the PDF of this article at: https://the-jci/article.php?id=34780

Understanding the genetics of congenital hyperinsulinism

A number of congenital disorders characterized by low blood sugar levels (hypoglycemia) as a result of excessive secretion of the hormone insulin are collectively known as congenital hyperinsulinism. These disorders are caused by genetic mutations that result in mutant KATP channel proteins in the insulin-secreting cells of the pancreas. To develop the most common and most severe form of congenital hyperinsulinism a baby must inherit a mutated gene from each of its parents (these mutations are said to be recessive as if only one mutated gene is inherited the baby does not suffer from the disease). Recent reports have suggested that less severe forms of the disease can arise in children through the inheritance of a mutated gene from only one parent (these mutations are said to be dominant as the mutated gene causes disease despite the presence of a normal version of the gene). To better understand the differences between the recessive and dominant mutations that cause congenital hyperinsulinism, Charles Stanley and colleagues, at the Children’s Hospital of Philadelphia, characterized 33 patients with dominantly inherited KATP mutations.

Consistent with the recent reports on a small number of children, the authors found that patients with disease caused by dominant mutations exhibited a milder hypoglycemia than is normal for individuals with congenital hyperinsulinism caused by recessive mutations. Indeed, there were a large number of asymptomatic individuals and disease in most symptomatic individuals was well controlled with medication. Mechanistic insight into the difference in the severity of disease caused by dominant and recessive mutations was provided by the observation that dominant mutations generated a form of KATP that can reach the cell surface but has impaired activity, whereas recessive mutations are known to generate a form of KATP that cannot reach the cell surface. The authors stress that because children with dominant KATP mutations are likely to exhibit less severe symptoms, the disease may be missed and doctors should carefully evaluate children with family histories of the disease.

TITLE: Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations

Charles A. Stanley
The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

View the PDF of this article at: https://the-jci/article.php?id=35414

New insight into the mechanisms underlying congential hypothyroidism

The generation of thyroid hormones, which are essential for normal development, is dependent on the proper secretion of the protein thyroglobulin. Thyroglobuin is a large protein with several distinct regions, including one known as region I-II-III and one known as the ChEL domain. Mutations in the ChEL domain have been linked to congenital hypothyroidism. However, the exact mechanisms by which these mutations alter thyroglobulin secretion are unknown. A new study by Peter Arvan and colleagues, at the University of Michigan, Ann Arbor, has revealed that ChEL seems to have two functions that enable thryroglobulin secretion – it ensures region I-II-III is folded correctly and it escorts the correctly folded protein out of the cell. The authors hope that these insights into the functions of the ChEL domain of thyroglobulin might help uncover new potential therapeutic targets for the treatment of congenital hypothyroidism.

TITLE: The cholinesterase-like domain of thyroglobulin functions as an intramolecular chaperone

Peter Arvan
University of Michigan, Ann Arbor, Michigan, USA.

View the PDF of this article at: https://the-jci/article.php?id=35164

Source: Karen Honey

Journal of Clinical Investigation

American Lung Association Supports Department Of Housing And Urban Development Recommendation On Non-Smoking Policies In Public Housing

Statement of Charles D. Connor, American Lung Association President and CEO:

The U.S. Department of Housing and Urban Development’s (HUD) Office of Healthy Homes and Lead Hazard Control and its Office of Public and Indian Housing issued new recommendations for non-smoking policies for public housing. These recommendations strongly encourage Public Housing Authorities to enact non-smoking policies in some or all of their public housing units.

The American Lung Association applauds HUD on these important recommendations that could result in protection for residents of public housing across the country, especially children, the elderly and people with chronic lung diseases. Residents of public housing are among those most at risk from unhealthy air from a variety of factors, including a high prevalence of secondhand smoke. The Lung Association strongly recommends that all public housing units adopt non-smoking policies to ensure no one – especially children, the elderly and those with chronic diseases – has to breathe dangerous secondhand smoke.

Because tobacco smoke can migrate between units in multiunit housing, it can cause respiratory illness, heart disease, cancer, and other adverse health effects in neighboring families. Exposure to secondhand smoke impedes the development of a child’s lungs, aggravates asthma, often resulting in hospitalizations, and causes scores of other health problems. Smoking is also a major cause of fires and fire-related deaths and injuries.

Secondhand smoke is particularly harmful to children, whose lungs are still developing. A 2007 Johns Hopkins University study of home indoor pollutant exposure among inner city children found that between 57 and 60 percent of these children lived with at least one person who smoked.

The Lung Association also recommends increased smoking cessation support through public health programs, especially Medicaid, to more effectively reduce exposure to smoke among this very vulnerable population. As the HUD memo noted, the Lung Association maintains information on tobacco cessation coverage and services provided in each state at lungusa/cessationcoverage.

The HUD notice is posted at hud/offices/pih/publications/notices/09/pih2009-21.pdf.

The American Lung Association

Indianapolis Discovery Network For Dementia: Building Efficient, Effective, Locally Sensitive Solutions For Dementia Care

Dementia is a growing burden for society, propelling patients and caregivers to increasingly use the health-care system. A year ago, local researchers, health-care professionals, and community advocates came together to form the Indianapolis Discovery Network for Dementia (IDND) to enhance dementia care in the nation’s twelfth largest city.

On Oct. 20, IDND will launch RAPID-PC – Recognizing and Assessing the Progression of Cognitive Impairment and Dementia in Primary Care with a summit meeting for researchers, clinicians, nurses, nurse practitioners and physician assistants to share experiences and progress.

The group is drawing upon unique features of the Indianapolis health-care environment, the most wired in the nation, to develop a model which they believe other communities can use to enhance the delivery of dementia care.

“If tomorrow we developed a breakthrough in dementia treatment such as a vaccine, it would take 17 years and $800 million for that development to become available as a prescription and it would reach only a fraction of those who could benefit from it. That isn’t acceptable,” said Malaz Boustani, M.D., M.P.H., an assistant professor of medicine at Indiana University School of Medicine, an Indiana University Center for Aging Research investigator and a Regenstrief Institute research scientist. Dr. Boustani, IDND’s chief research officer, bases his estimates on a systematic review of drug development literature.

According to Dr. Boustani, in the state of Indiana, which he says is representative of the U.S. as a whole, 60 percent of people with dementia or pre-dementia (also known as mild cognitive impairment) are not recognized as having these conditions when they go to a hospital and 80 percent are not recognized as having dementia or pre-dementia by their primary care physicians. The result is that less than 10 percent receive medications appropriate to their level of cognitive impairment and approximately a quarter receive medications which are inappropriate.

“Nationwide, the health-care system is not delivering good dementia care because we have not presented a comprehensive assessment of the biopsychosocial needs of a person with dementia and have not followed up with solutions that are sensitive to local community needs and resources,” said Dr. Boustani, who is a geriatrician. Eight out of 10 individuals with dementia living in the community have significant behavioral and/or psychological symptoms that require medical and psychological care.

He also notes that caregivers have been largely ignored in spite of the fact that they provide millions of unpaid care hours per year (180 million hours valued at $1.7 trillion in Indiana in 2005) and are hospitalized at a very high rate (24 percent over a six-month period in Indiana) .

With Rapid-PC, IDND is taking a major step toward its goal of building efficient, effective, locally sensitive solutions for dementia care.